Fluoroether compositions and methods for inhibiting their degradation in the presence of a Lewis acid

ABSTRACT

The present invention relates to an anesthetic composition containing a fluoroether compound and a physiologically acceptable Lewis acid inhibitor. This composition exhibits improved stability and does not readily degrade in the presence of a Lewis acid.

This application is a continuation of U.S. Ser. No. 09/447,853 filedNov. 23, 1999, now U.S. Pat. No. 6,288,127, which was a continuation ofU.S. Ser. No. 08/789,679 filed Jan. 27, 1997, now U.S. Pat. No.5,990,176.

TECHNICAL FIELD OF THE INVENTION

The present invention relates generally to stable, anestheticfluoroether compositions that do not degrade in the presence of a Lewisacid. The present invention also relates to a method of inhibiting thedegradation of fluoroethers in the presence of Lewis acids.

BACKGROUND OF THE INVENTION

Fluoroether compounds are commonly employed as anesthetic agents.Examples of fluoroether compounds used as anesthetic agents includesevoflurane (fluoromethyl-2,2,2-trifluoro-1-(trifluoromethyl)ethylether), enflurane ((±)-2-chloro-1,1,2-trifluoroethyl difluoromethylether), isoflurane (1-chloro-2,2,2-trifluoroethyl difluoromethyl ether),methoxyflurane (2,2-dichloro-1,1-difluoroethyl methyl ether), anddesflurane ((±)-2-difluoromethyl 1,2,2,2-tetrafluoroethyl ether).

Although fluoroethers are excellent anesthetic agents, it has beendiscovered that some fluoroethers experience stability problems. Morespecifically, it has been determined that certain fluoroethers, in thepresence of one or more Lewis acids, degrade into several productsincluding potentially toxic chemicals such as hydrofluoric acid.Hydrofluoric acid is toxic by ingestion and inhalation and is highlycorrosive to skin and mucous membranes. Thereupon, the degradation offluoroethers to chemicals such hydrofluoric acid is of great concern tothe medical community.

Degradation of fluoroethers has been found to occur in glass containers.The degradation of fluoroethers in glass containers is believed to beactivated by trace amounts of Lewis acids present in the container. Thesource of the Lewis acids can be aluminum oxides, which are a naturalcomponent of glass. When the glass wall becomes altered or etched insome manner, the aluminum oxide become exposed and come into contactwith the contents of the container. The Lewis acids then attack thefluoroether and degrade it.

For example, when the fluoroether sevoflurane is contacted with one ormore Lewis acids in a glass container under anhydrous conditions, theLewis acid initiates the degradation of sevoflurane to hydrofluoric acidand several degradation products. The degradation products ofsevoflurane are hexafluoroisopropyl alcohol, methyleneglycolbishexafluoroisopropyl ether, dimethyleneglycol bishexafluoroisopropylether and methyleneglycol fluoromethyl hexafluoroisopropyl ether. Thehydrofluoric acid proceeds to further attack the glass surface andexpose more of the Lewis acid on the glass surface. This results infurther degradation of sevoflurane.

The degradation mechanism of sevoflurane in the presence of a Lewis acidcan be illustrated as follows:

Abbv. Compound Name Structure HFIP hexafluoroisopropyl alcohol(CF₃)₂CHOH P1 methyleneglycol bishexafluoroisopropyl(CF₃)₂CHOCH₂OCH(CF₃)₂ ether P2 dimethyleneglycol bishexafluoroisopropyl(CF₃)₂CHOCH₂OCH(CF₃)₂ ether S1 methyleneglycol fluoromediyl(CF₃)₂CHOCH₂OCH₂F hexafluoroisopropyl ether

Therefore, a need exists in the art for a stable anesthetic compositioncontaining fluoroether compounds that does not degrade in the presenceof a Lewis acid.

SUMMARY OF THE INVENTION

The present invention involves a stable anesthetic composition thatcontains a fluoroether compound having an alpha fluoroether moietyhaving added thereto an effective stabilizing amount of a Lewis acidinhibitor. The preferred fluoroether compound is sevoflurane and thepreferred Lewis acid inhibitor is water. The composition can be preparedby adding the Lewis acid inhibitor to the fluoroether compound, byadding the fluoroether compound to the Lewis acid inhibitor, or bywashing a container with the Lewis acid inhibitor and then adding thefluoroether compound.

The present invention also involves a method for stabilizing afluoroether compound having an alpha fluoroether moiety. The methodinvolves adding an effective stabilizing amount of a Lewis acidinhibitor to the fluoroether compound to prevent the degradation of thefluoroether compound by a Lewis acid. The preferred fluoroether compoundis sevoflurane and the preferred Lewis acid inhibitor is water.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows a chromatogram demonstrating that in the presence of thesame amount of aluminum oxide (50 mg), the degradation of sevofluranedecreases with increasing amounts of water. The identified degradationproducts of sevoflurane shown in FIG. 1 are hexafluoroisopropyl alcohol(HFIP), methyleneglycol bishexafluoroisopropyl ether (P1),dimethyleneglycol bishexafluoroisopropyl ether (P2) and methyleneglycolfluoromethyl hexafluoroisopropyl ether (S1).

FIG. 2 depicts a chromatogram showing the degradation of sevofluraneafter heating in an autoclave at 119° C. for 3 hours.

FIG. 3 depicts a chromatogram showing the effects of water on theinhibition of the degradation of sevoflurane after heating in anautoclave at 119° C. for 3 hours.

FIG. 4 shows a bar graph comparing the sevoflurane degradant P2 inactivated type m amber glass bottles from Examples 5 and 6. The graphdemonstrates that the degradation of sevoflurane is inhibited by theaddition of 400 ppm of water.

FIG. 5 shows a bar graph comparing the sevoflurane degradant S1 inactivated type III amber glass bottles from Examples 5 and 6. The graphshows that the degradation of sevoflurane is inhibited by the additionof 400 ppm of water.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a stable, anesthetic composition thatdoes not degrade in the presence of a Lewis acid. The present inventionalso relates to methods of preparing said anesthetic composition.

The anesthetic composition of the present invention contains at leastone fluoroether compound. The fluoroether compound used in thecomposition corresponds to Formula I, below.

In Formula I, each R₁; R₂; R₃; R₄; and R₅ can independently be ahydrogen, halogen, an alkyl group having from 1 to 4 carbon atoms (C₁-C₄alkyl), or a substituted alkyl having from 1 to 4 carbon atoms (C₁-C₄substituted alkyl). In the preferred embodiment of Formula I, R₁ and R₃are each the substituted alkyl CF₃ and R₂, R₄ and R₅ are each ahydrogen.

As used herein, the term “alkyl” refers to a straight or branched chainalkyl group derived from saturated hydrocarbons by the removal of onehydrogen atom. Examples of alkyl groups include methyl, ethyl, n-propyl,isopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, and the like. Asused herein, the term “substituted alkyl” refers to an alkyl groupsubstituted by one or more groups such as halogen, amino, methoxy,difluoromethyl, trifluoromethyl, dichloromethyl, chlorofluoromethyl,etc. As used herein, the term “halogen” refers to one of theelectronegative elements of group VIIA of the periodic table.

The fluoroether compounds having the Formula I contain the alphafluoroether moiety —C—O—C—F—. Lewis acids attack this moiety whichresults in the degradation of the fluoroether to various degradationproducts and toxic chemicals.

Examples of fluoroether compounds of Formula I that can be used in thepresent invention are sevoflurane, enflurane, isoflurane, methoxyfluraneand desflurane. The preferred fluoroether compound for use in thepresent invention is sevoflurane.

Methods for making the fluoroether compounds having Formula I are wellknown in the art and can be used in preparing the composition of thepresent invention. For example, sevoflurane can be prepared using themethods described in U.S. Pat. No. 3,689,571 and U.S. Pat. No. 2,992,276herein incorporated by reference.

The composition of the present invention contains a total of from about98% w/w to about 100% w/w of a fluoroether compound having the FormulaI. Preferably, the composition contains at least 99.0% w/w of thefluoroether compound.

The anesthetic composition of the present invention also contains aphysiologically acceptable Lewis acid inhibitor. As used herein, “Lewisacid inhibitor” refers to any compound that interacts with the emptyorbital of a Lewis acid thereby blocking the potential reaction sites ofthe acid. Any physiologically acceptable Lewis acid inhibitor can beused in the composition of the present invention. Examples of Lewis acidinhibitors that can be used in the present invention include water,butylated hydroxytoluene (1,6-bis(1,1-dimethyl-ethyl)-4-methylphenol),methylparaben (4-hydroxybenzoic acid methyl ester), propylparaben(4-hydroxybenzoic acid propyl ester), propofol (2,6-diisopropyl phenol)and thymol (5-methyl-2-(1-methylethyl)phenol).

The composition of the present invention contains an effectivestabilizing amount of a Lewis acid inhibitor. It is believed that theeffective stabilizing amount of Lewis acid inhibitor that can be used inthe composition is about 0.0150% w/w (water equivalent) to about thesaturation level of the Lewis acid inhibitor in the fluoroethercompound. As used herein, the term “saturation level” means the maximumsolubility level of the Lewis acid inhibitor in the fluoroethercompound. It will be appreciated that the saturation level may betemperature dependent The saturation level also will depend on theparticular fluoroether compound and the particular Lewis acid inhibitorbeing used in the composition. For example, when the fluoroethercompound is sevoflurane and the Lewis acid inhibitor is water, theamount of water employed to stabilize the composition is believed to befrom about 0.0150% w/w to about 0.14% w/w (saturation level). It shouldbe noted, however, that once the composition is exposed to Lewis acids,the amount of Lewis acid inhibitor in the composition may decrease asthe Lewis acid inhibitor reacts with the Lewis acid to prevent theunwanted degradative reaction of Lewis acid inhibitor with thecomposition.

The Lewis acid inhibitor preferred for use in the composition of thepresent invention is water. Purified or distilled water or a combinationof both can be used. As stated earlier, the effective amount of waterthat can be added to the composition is believed to be about 0.0150% w/wto about 0.14% w/w, and is preferably about 0.0400% w/w to about 0.0800%w/w. For any other Lewis acid inhibitor, a molar equivalent based uponmoles of water should be used.

When the fluoroether compound is exposed to a Lewis acid, thephysiologically acceptable Lewis acid inhibitor present in thecomposition donates electrons to the empty orbital of the Lewis acid andforms a covalent bond between the inhibitor and the acid. Thereupon, theLewis acid is prevented from reacting with the alpha fluoroether moietyof the fluoroether and degrading the fluoroether.

The composition of the present invention can be prepared in severalways. In one aspect, a container, such as a glass bottle, is firstwashed or rinsed with the Lewis acid inhibitor and then filled with thefluoroether compound. Optionally, the container may be partially driedafter the washing or rinsing. Once the fluoroether is added to thecontainer, the container is sealed. As used herein, the term “partiallydried” refers to an incomplete drying process that leaves a residual ofa compound on or in the container being dried. Also as used herein, theterm “container” refers to a receptacle made from glass, plastic, steelor other material that can be used for holding goods. Examples ofcontainers include bottles, ampules, test tubes, beakers, etc.

In another aspect, the Lewis acid inhibitor is added to a driedcontainer prior to filling the container with the fluoroether compound.Once the Lewis acid inhibitor has been added, the fluoroether compoundis added to the container. Alternatively, the Lewis acid inhibitor maybe added directly to a container already containing the fluoroethercompound.

In another aspect, the Lewis acid inhibitor may be added to a containerfilled with the fluoroether compound under humid conditions. Forexample, water can be added to a container filled with the fluoroethercompound by placing the container in a humidity chamber for a sufficientamount of time to allow the water to accumulate in the container.

The Lewis acid inhibitor can be added to the composition at anyappropriate point in the manufacturing process, e.g., at the finalmanufacturing step before filling into shipping containers, e.g., 500liter shipping container. Appropriate quantities of the composition canbe dispensed from the container and packaged in containers of moresuitable size for use in the industry, such as 250 mL glass bottles.Additionally, small quantities of the composition containing appropriateamounts of the Lewis acid inhibitor can be used to wash or rinsecontainers to neutralize any Lewis acids that might be present in thecontainer. Once the Lewis acids have been neutralized, the container maybe emptied and additional quantities of the fluoroether compositionadded to the container prior to sealing the container.

By way of example, but not of limitation, examples of the presentinvention will now be given.

EXAMPLE 1 Activated Alumina as a Lewis Acid

Type III glass consists mainly of silicon dioxide, calcium oxide, sodiumoxide and aluminum oxide. Aluminum oxide is a known Lewis acid. Theglass matrix is normally inert to sevoflurane. However, under certainconditions (anhydrous, acidic), the glass surface can be attacked oraltered, exposing sevoflurane to active Lewis acid sites such asaluminum oxide.

The effect of water on the degradation of sevoflurane was studied byadding various amounts of activated alumina to 20 ml of sevofluranecontaining the following three levels of moisture: 1) 20 ppmwater—measured water, no additional water added; 2) 100 ppm—spiked; and3) 260 ppm water—spiked. Table 1 below shows the experimental matrix.

TABLE 1 1 2 3 A 50 mg Al₂O₃ 50 mg Al₂O₃ 50 mg Al₂O₃ 20 ppm Water 100 ppmWater 260 ppm Water B 20 mg Al₂O₃ 20 mg Al₂O₃ 20 mg Al₂O₃ 20 ppm Water100 ppm Water 260 ppm Water C 10 mg Al₂O₃ 10 mg Al₂O₃ 10 mg Al₂O₃ 20 ppmWater 100 ppm Water 260 ppm Water

It will be appreciated that 20 ppm Water is equivalent to 0.0022% w/wWater. The samples were placed at 60° C. and analyzed by gaschromatography after 22 hours. FIG. 1 shows that in the presence of thesame amount of aluminum oxide (50 mg) that the degradation ofsevoflurane decreases with increasing amounts of water (Row A from Table1). A similar trend was observed for 20 mg and 10 mg of aluminum oxide(Rows B and C).

EXAMPLE 2

Degradation in Ampules of Sevoflurane by Heat with and without theAddition of Water.

Approximately 20 mL of sevoflurane was added to a 50 mL Type I clearampule and approximately 20 mL of sevoflurane and 1300 ppm of water wasadded to a second ampule. Both ampules were flame-sealed and thenautoclaved at 119° C. for three hours. The contents of the two ampuleswere then analyzed by gas chromatography. FIG. 2 shows that thesevoflurane in the first ampule degraded. FIG. 3 shows that thesevoflurane in the second ampule did not degrade as a result of theLewis acid inhibitor, namely the added water.

EXAMPLE 3

Degradation of Sevoflurane in Ampules using Water-Spiked Studies (109ppm to 951 ppm)

Type I clear glass ampules were used to study the effect of variouslevels of water in inhibiting the degradation of sevoflurane.Approximately 20 mL of sevoflurane and different levels of water rangingfrom about 109 ppm to about 951 ppm were added to each ampule. Theampules were then sealed. A total of ten ampules were filled withsevoflurane and varying amounts of water. Five of the ampules wereincluded in Set A and the other five ampules were included in Set B. Theampules were then autoclaved at 119° C. for three hours. Samples in SetA were placed on a mechanical shaker overnight to allow the moisture tocoat the glass surface. Samples in Set B were prepared withoutequilibrating the water with the glass surface. Several control sampleswere also prepared. Two non-autoclaved ampules (Control Ampule 1 andControl Ampule 2) and a bottle (Control bottle) were each filled with 20mL of sevoflurane. No water was added to any of the control samples.Also, the controls samples were not shaken overnight The levels ofhexafluoroisopropanol (HFIP) and total degradants (includingmethyleneglycol bishexafluoroisopropyl ether, dimethyleneglycolbishexafluoroisopropyl ether, methyleneglycol fluoromethyl hexafluoroisopropyl ether) were measured by gas chromatography. The results areshown below in Table 2.

TABLE 2 Total Mois- Total Degra- ture Calcu- HFIP dants with- Samplelated (ppm) pH (ppm) out HFIP (ppm) Control, Bottle 6.0 6 57 Control,Ampule 1, RT 3.0 7 50 Control, Ampule 2, RT 4.0 6 51 Set A (ShakenOvernight) 1 109 0 1,525 201614 2 206 0 2,456 105518 3 303 0 4,027127134 4 595 5.0 7 82 5 951 5.0 12 84 Set B (Not Shaken) 1 109 0 1,936195364 2 206 0 3,390 170869 3 303 0 5,269 101845 4 595 6.0 21 107 5 9516.0 10 63

The results in Table 2 above demonstrate that for the ampules in Set Aand in Set B, at least 595 ppm of water was sufficient to inhibit thedegradation of sevoflurane. The results show no significant differencebetween the ampules that were shaken overnight and those that were notshaken overnight

EXAMPLE 4 Degradation of Sevoflurane in Ampules Using Water SpikedSevoflurane Studies at 60° C. or 40° C.

Type I clear glass ampules were employed to study the effect of variouslevels of water and temperature in inhibiting the degradation ofsevoflurane. Approximately 20 mL of sevoflurane and different levels ofwater ranging from about 109 ppm to about 951 ppm were added to eachampule. The ampules were then flame-sealed. To accelerate thedegradation process, samples from each moisture level were placed at twoheating conditions. Samples were placed on a 60° C. stability stationfor 144 hours or placed on a 40° C. stability station for 200 hours. Theresulting sevoflurane in each of the samples was analyzed by gaschromatography and pH. Hexafluoroisopropyl alcohol (HFIP) and the totaldegradants of sevoflurane were measured. The results are shown below inTable 3.

TABLE 3 HFIP Total Degradants Sample Total Moisture pH (ppm) (ppm)Water-spiked, 60° C., 144 hrs 1 109 0 850 474796 2 206 3.5 7 48 8 65 3-1303 3.5 13 68 16 88 3-2 303 5.0 8 60 4 595 5.5 7 66 5-1 951 5.5 4 52 5-2951 5.5 5 60 Water-spiked, 40° C., 200 hrs 6-1 No H₂O added 0 232 1024356-2 No H₂O added 2.5 24 68 7 109 3.0 40 77 8 206 5.0 7 59 9 303 5.0 6 5910  595 6.0 6 60 11  951 6.0 5 60

The results in Table 3 demonstrate that at 40° C. for 200 hours, waterlevels higher than 206 ppm inhibit the degradation of sevoflurane. Forsamples stored at 60° C. for 144 hours or longer, water levels higherthan 303 ppm inhibit the degradation of sevoflurane. This data suggeststhat as the temperature increases, the amount of water required toinhibit the degradation of sevoflurane will increase.

EXAMPLE 5 Sevoflurane Degradation in Activated Type III Amber GlassBottles

Type III amber glass bottles that were used to store degradedsevoflurane were examined. Those bottles that exhibited a significantamount of etching inside the bottle were selected. A total of ten TypeIII amber glass bottles were selected. The degraded sevofluranecontained in each of these bottles was drained and the bottles wererinsed several times with non-degraded fresh sevoflurane. Approximately100 mL of non-degraded sevoflurane containing about 20 ppm water wasadded to each bottle. Gas chromatography analysis for all the sampleswas performed at the time zero and after heating at 50° C. for 18 hours.Hexafluoroisopropyl (HFIP) and dimethyleneglycol ether (P2) weremeasured. The results are shown in Tables 4 and 5 below.

TABLE 4 Results at Time Zero Degradation Products (ppm) Bottle NumberHFIP P2 Total 1 124  <10 185 2 84 <10 123 3 77 <10 137 4 56 <10  89 5144  <10 190 6 63 <10  96 7 58 <10  95 8 60 <10 102 9 51 <10 106 10  65<10 140

TABLE 5 Results at 50° C., 18 Hours Degradation Products (ppm) BottleNumber HFIP P2 Total 1 1026 7938 14243 2  912 3013  6428 3 1160 466210474 4  908 3117  7381 5  907 6687 11774 6 1128 5448 11313 7 1152 2371 6695 8 1199 2925  7386 9 1560 4183 10325 10  1455 2255  6667

The results in Tables 4 and 5 show that the glass surfaces in thesebottles were “activated” by degraded sevoflurane. “Activated” glasssurfaces thus served as initiators for the degradation of freshsevoflurane.

EXAMPLE 6 Additional Studies of Sevoflurane Degradation In ActivatedType III Amber Glass Bottles

The extent of the degradation of sevoflurane in each of the bottles fromExample 5 were quantified by gas chromatography. The ten bottles weredivided into two groups, the Control Sevo Group (containing bottles 2,3, 5, 7, 8) and the Study Sevo Group (containing Bottles 1, 4, 6, 9,10).

All ten bottles were re-rinsed several times with non-degradedsevoflurane containing about 20 ppm of water. For the five Control SevoGroup bottles, 100 mL of sevoflurane containing about 20 ppm of waterwas added to each bottle. For the five Study Group bottles, 100 mL ofsevoflurane containing about 400 ppm of water (spiked) was added to eachbottle.

Gas chromatography for all samples was performed at time zero and afterheating at 50° C. for 18 hours. Hexafluoroisopropyl alcohol (HFIP),dimethyleneglycol bishexafluoroisopropyl ether (P2) and total degradantswere measured. The results are shown below in Table 6.

TABLE 6 Results at the Zero Hour and Eighteen Hours Degradation Products(ppm) HFIP P2 Total Time 0 hour 18 hour 0 hour 18 hour 0 hour 18 hourControl Group (20 ppm water) 2 <10 777 <10 2291 <50 5995 3 <10 790 <102714 <50 6552 5 11 688 <10 2446 <50 5485 7 <10 894 <10 1171 <50 4124 8<10 824 <10 1950 <50 5139 Study Group (400 ppm water) 1 12 605 <10 <10<50 669 4 <10 84 <10 <10 <50 98 6 <10 331 <10 <10 <50 357 9 <10 294 <10<10 <50 315 10  10 528 <10 <10 <50 577

The results in Table 6 show that at zero hour, no significantdegradation of sevoflurane was observed when compared to that of thezero-hour results in Table 4. The results in Table 6 show that, in theStudy Sevo Group (400 ppm water), the degradation of sevoflurane wassignificantly reduced. The amounts of degradants P2 (dimethyleneglycolbishexafluoroisopropyl ether) and S1 (methyleneglycol fluoromethylhexafluoroisopropyl ether)were much less than those in Control Group 1(20 ppm water). The HFIP concentration in the study Sevo Group, however,was quite high and suggests that the glass surfaces were still somewhatactive.

FIG. 4 shows a graphic comparison of the degradant dimethyleneglycolbishexafluoroisopropyl ether (P2) from the data in Tables 5 and 6. FIG.5 shows a graphic comparison of the degradant methyleneglycolfluoromethyl hexafluoroisopropyl ether (S1) as it appears in Examples 5and 6. Both FIG. 4 and FIG. 5 demonstrate that the degradation ofsevoflurane is inhibited by the addition of water at 400 ppm.

EXAMPLE 7 Additional Studies of Sevoflurane Degradation In ActivatedType III Amber Glass Bottles

Sevoflurane was decanted from the five bottles of the Study Sevo Groupfrom Example 6. Each bottle was rinsed thoroughly with freshsevoflurane. Approximately 125 mL of water-saturated sevoflurane wasthen put into each bottle. The five bottles were then placed on amechanical roller for approximately two hours to allow the water to coatthe activated glass surfaces. The water-saturated sevoflurane was thendrained form each bottle and replaced by 100 mL of sevofluranecontaining 400 (spiked) ppm of water. Gas chromatography analysis forall samples was performed after heating at 50° C. for 18 hours, 36hours, and 178 hours. Bishexafluoroisopropyl ether (P2) and totaldegradants were measured. The results are shown below in Table 7.

TABLE 7 Degradation Products (ppm) HFIP P2 Total Degradants Time 36 hour178 hour 36 hour 178 hour 36 hour 178 hour Study Group (400 ppm water) 1<10 16 <10 <10 <50 <50 4 <10 <10 <10 <10 <50 <50 6 <10 28 <10 <10 <50<50 9 <10 15 <10 <10 <50 <50 10  <10 19 <10 <10 <50 <50

The results in Table 7 demonstrate that the degradation of sevofluranewas greatly inhibited by treating the activated glass surface with watersaturated-sevoflurane prior to heating.

What is claimed is:
 1. A method for preventing degradation by Lewisacids of a quantity of sevoflurane, said method comprising providing aquantity of sevoflurane and contacting said quantity of sevoflurane withan amount of Lewis acid inhibitor, said amount of Lewis acid inhibitorbeing selected such that said Lewis acid inhibitor is present in anamount of at least 150 parts per million parts of a total of saidquantity of sevoflurane and said amount of Lewis acid inhibitor.
 2. Amethod in accordance with claim 1, wherein said Lewis acid inhibitor isselected from a group consisting of water, butylated hydroxytoluene,methylparaben, propylparaben, propofol, and thymol.
 3. A method inaccordance with claim 1, wherein said Lewis acid inhibitor is water. 4.A sevoflurane product protected from degradation by Lewis acids inaccordance with the method of claim
 1. 5. A sevoflurane productprotected from degradation by Lewis acids in accordance with the methodof claim
 2. 6. A sevoflurane product protected from degradation by Lewisacids in accordance with the method of claim 3.